The Middle Ear Muscle Reflex in Rat: Developing a Biomarker of Auditory Nerve Degeneration.

OBJECTIVES: The long-term goal of this research is to determine whether the middle ear muscle reflex can be used to predict the number of healthy auditory nerve fibers in hearing-impaired ears. In this study, we develop a high-impedance source and an animal model of the middle ear muscle reflex and explore the influence of signal frequency and level on parameters of the reflex to determine an optimal signal to examine auditory nerve fiber survival. DESIGN: A high-impedance source was developed using a hearing aid receiver attached to a 0.06 diameter 10.5-cm length tube. The impedance probe consisted of a microphone probe placed near the tip of a tube coupled to a sound source. The probe was calibrated by inserting it into a syringe of known volumes and impedances. The reflex in the anesthetized rat was measured with elicitor stimuli ranging from 3 to 16 kHz presented at levels ranging from 35 to 100 dB SPL to one ear while the reflex was measured in the opposite ear containing the probe and probe stimulus. RESULTS: The amplitude of the reflex increased with elicitor level and was largest at 3 kHz. The lowest threshold was approximately 54 dB SPL for the 3-kHz stimulus. The rate of decay of the reflex was greatest at 16 kHz followed by 10 and 3 kHz. The rate of decay did not change significantly with elicitor signal level for 3 and 16 kHz, but decreased as the level of the 10-kHz elicitor increased. A negative feedback model accounts for the reflex decay by having the strength of feedback dependent on auditory nerve input. The rise time of the reflex varied with frequency and changed with level for the 10- and 16-kHz signals but not significantly for the 3-kHz signal. The latency of the reflex increased with a decrease in elicitor level, and the change in latency with level was largest for the 10-kHz stimulus. CONCLUSIONS: Because the amplitude of the reflex in rat was largest with an elicitor signal at 3 kHz, had the lowest threshold, and yielded the least amount of decay, this may be the ideal frequency to estimate auditory nerve survival in hearing-impaired ears.

Cochlear hearing loss in patients with Laron syndrome.

The aim of this prospective clinical study was to test auditory function in patients with Laron syndrome, either untreated or treated with insulin-like growth factor I (IGF-I). The study group consisted of 11 patients with Laron syndrome: 5 untreated adults, 5 children and young adults treated with replacement IGF-I starting at bone age <2 years, and 1 adolescent who started replacement therapy at bone age 4.6 years. The auditory evaluation included pure tone and speech audiometry, tympanometry and acoustic reflexes, otoacoustic emissions, loudness dynamics, auditory brain stem responses and a hyperacusis questionnaire. All untreated patients and the patient who started treatment late had various degrees of sensorineural hearing loss and auditory hypersensitivity; acoustic middle ear reflexes were absent in most of them. All treated children had normal hearing and no auditory hypersensitivity; most had recordable middle ear acoustic reflexes. In conclusion, auditory defects seem to be associated with Laron syndrome and may be prevented by starting treatment with IGF-I at an early developmental age.

[The delayed sensitization of CRH response developed after chronic variable stress on the acoustic startle reflex].

Substantial evidence indicates that brain neurons containing and secreting norepinephrine (NE) and corticotrophin-releasing hormone (CRH) are activated during stress. The acoustic startle reflex (ASR) can be enhanced by CRH neuronal activity in the central nucleus of the amygdala. Our previous study demonstrates an augmentation of the footshock-induced ASR (f-ASR) 1 day after chronic variable stress (CVS) for 13 days. In this study, to evaluate a long-term neural plasticity in NE-CRH systems after CVS, we examined f-ASR 1, 8 or 15 days after CVS. The augmented magnitude of the f-ASR 15 day after CVS was potentiated and delayed compared with that 1 day after CVS. The delayed augmentation of f-ASR was inhibited by repeated treatment with desipramine, maprotiline or paroxetine for 14 days after CVS. A single treatment with any antidepressant agent had no influence the f-ASR while a marked inhibition by a single dose of alprazolam, CRH1-receptor antagonist, prazosin and propranolol was observed. The decreased tyrosine hydroxylase activity in the locus coeruleus and the beta-adrenoceptor down-regulation in the amygdaloid complex might be involved in the inhibiton of the delayed augmentation of f-ASR by repeated antidepressant treatment, leading to the possibility that the delayed sensitization of CRH response to stress after CVS might contribute to the biological mechanism underlying the formation of pathological states such as anxiety and depressive disorders.

Effects of developmental fluoride exposure on rat ultrasonic vocalization, acoustic startle reflex and pre-pulse inhibition.

Rats receiving fluoride during the whole pregnancy up to the 9th day of lactation showed, when isolated at 10th day of life, a reduced rate of ultrasonic vocalizations (UV) in male pups (NaF 5.0 mg) and, in 90th days male rats, an increase of the Pre-Pulse Inhibition (PPI) with a reduction of the Peak response to the Startle stimulus given alone. Newborn rat reactivity could represent a useful and validated model in anxiety studies which could be moored with the Acoustic Startle Reflex (ASR) and PPI, appropriate models to study, in adulthood, particular neurological and psychiatric disorders showing deficits in attention and sensory-motor gating (Tourettes' syndrome, obsessive compulsive disorders, Huntington's disease and schizophrenia).

Excitatory and inhibitory effects of serotonin on sensorimotor reactivity measured with acoustic startle.

Serotonin infused into the lateral ventricle in rats produced a dose-dependent depression of the acoustic startle reflex. When infused onto the spinal cord, serotonin produced a dose-dependent increase in startle. Thus the same neurotransmitter can modulate the same behavior in opposite ways, depending on which part of the central nervous system is involved.

Dose-dependent suppression of the electrically elicited stapedius reflex by general anesthetics in children undergoing cochlear implant surgery.

BACKGROUND: Cochlear implants stimulate the auditory nerve to enable hearing. Determining appropriate upper and lower limits of stimulation is essential for successful cochlear implantation. The intraoperative evoked stapedius reflex threshold (ESRT) and evoked compound action potential (ECAP) are commonly used to determine the limits of implant stimulation. In this study, we evaluated the dose-related effects of sevoflurane, desflurane, isoflurane, and propofol on the intraoperative ESRT and ECAP. METHODS: Forty-four children aged 6 mo to 17 yr undergoing cochlear implantation were recruited. Each child was randomly assigned to receive sevoflurane, desflurane, isoflurane, or propofol. Evoked responses were measured by a blinded investigator at end-tidal anesthetic concentrations corresponding to 0, 0.75, and 1.5 age-adjusted minimum alveolar concentration administered in random sequence and at targeted blood concentrations of propofol of 0, 1.5, and 3.0 microg/mL. Data were analyzed using one-way repeated-measures analysis of variance. P < 0.05 was considered statistically significant. RESULTS: The ESRT increased dose dependently with increasing volatile anesthetic concentration (P < 0.01). The stapedius reflex was completely abolished by volatile anesthesia in more than half of children. Propofol minimally affected the ESRT. In contrast, the ECAP was unaffected by anesthesia. CONCLUSIONS: Volatile anesthetics suppress the stapedius reflex in a dose-dependent manner, suggesting that ESRT measurements acquired during volatile anesthesia will overestimate the maximum comfort level, which may cause discomfort postoperatively and adversely affect the child's adaptation to the implant. We advise against the use of volatile anesthetics for measurement of the stapedius reflex threshold during cochlear implant surgery.

Measuring the middle-ear reflex: A quantitative method to assess effects of industrial solvents on central auditory pathways.

Volatile organic solvents are frequently present in industrial atmospheres. Their lipophilic properties mean they quickly reach the brain following inhalation. Acute exposure to some solvents perturbs the middle ear reflex, which could jeopardize cochlear protection against loud noises. As the physiological mechanisms involved in this protective reflex are highly complex, in vivo rodent models are required to allow rapid and reliable identification of any adverse effects of solvents on the middle ear reflex (MER). In this study, MER amplitude was measured in anesthetized Brown-Norway rats by monitoring the decrease in distortion product otoacoustic emissions (DPOAEs) caused by a contralateral stimulation. Our screening test consisted in measuring the impact of inhalation of solvent vapors at 3000 ppm for 15 min on the MER amplitude. We had previously studied a selection of aromatic solvents with this model; here, we extended the analysis to volatile compounds from other chemical families. The results obtained shed light on the mechanisms involved in the interactions between solvents and their neuronal targets. Thus, benzene and chlorobenzene had the greatest effect on MER (≥ + 1.8 dB), followed by a group composed of toluene, styrene, p-xylene, m-xylene, tetrachloroethylene and cyclohexane, which had a moderate effect on the MER (between + 0.3 and + 0.7 dB). Finally, trichloroethylene, n-hexane, methyl-ethyl-ketone, acetone, o-xylene, and ethylbenzene had no effect on the MER. Thus, the effect of solvents on the MER is not simply linked to their lipophilicity, rather it depends on specific interactions with neuronal targets. These interactions appear to be governed by the compound's chemical structure, e.g. the presence of an aromatic ring and its steric hindrance. In addition, perturbation of the MER by a solvent is independent of its toxic effects on cochlear cells. As the MER plays a protective role against exposure to high-intensity noises, these findings could have a significant impact in terms of prevention for subjects exposed to both noise and solvents.

Acoustic startle reflex in rhesus monkeys: a review.

Modulation of the acoustic startle response is a simple and objective indicator of emotionality and attention in rodents and humans. This finding has proven extremely valuable for the analysis of neural systems associated with fear and anxiety. Until recently, there have been few efforts to develop acoustic startle measurement in non-human primates. Here we review recent work in which whole body acoustic startle amplitude has been measured in rhesus monkeys. Initial studies revealed that the amplitude of whole body startle in monkeys, as in rodents and humans, is directly proportional to acoustic stimulus intensity and gradually habituates with repeated exposures. Presentation of a weak acoustic stimulus 25-5,000 msec before a startle stimulus reduces startle amplitude by 40-50% depending on inter-stimulus interval length (prepulse inhibition). We have also measured significant fear-potentiated startle in the presence of a visual stimulus after pairing it with an inescapable pulse of pressurized air (fear-potentiated startle). This effect was reduced by diazepam and morphine, but not by buspirone. Ibotenic acid-induced lesions of the amygdala prevented the acquisition of fear-potentiated startle but, remarkably, did not prevent the expression of fear-potentiated startle when fear conditioning was carried out prior to the lesion. Finally, we have developed an objective measure of fear inhibition in monkeys using a novel conditioned inhibition procedure identical to one used in rats and humans. Our data demonstrate that acoustic startle in non-human primates successfully bridges rodent and human research. The opportunity now emerges to link concepts developed in rodents to the more complex neuroanatomical and cognitive processes common to monkeys and humans.

Nicotine effect on prepulse inhibition and prepulse facilitation in schizophrenia patients.

Acoustic prepulse inhibition (PPI) is considered an important biomarker in animal studies of psychosis and a number of psychiatric conditions. Nicotine has been shown to improve acoustic PPI in some animal strains and in humans. However, there is little data on effects of nicotine on acoustic PPI in schizophrenia patients using a double-blind, placebo-controlled study design. The primary aim of the current study was to test the effect of nicotine nasal spray on acoustic PPI in schizophrenia patients. The secondary aim was to test nicotine effect on prepulse facilitation (PPF). The study included 18 schizophrenia patient smokers and 12 healthy control smokers, tested in a double-blind, placebo-controlled, crossover, randomized design immediately after nicotine or saline placebo nasal sprays. PPI was tested using 120 ms prepulse-pulse interval. PPF was tested using 4500 ms prepulse-pulse interval. The results showed a significant main effect of drug on PPI in that nicotine improved PPI compared to placebo (p=0.008) with no drug by diagnosis interaction (p=0.90). Improvement in PPI in response to nicotine was significantly correlated with the baseline severity of clinical symptoms (r=0.59, p=0.02) in patients. There was no significant drug or drug by diagnosis interaction for the 4500 ms prepulse-pulse interval condition. However, nicotine improved inhibition in a subgroup of subjects exhibiting PPF (p=0.002). In conclusion, the findings confirmed that nicotine transiently improves acoustic PPI in schizophrenia patients. Additionally, schizophrenia patients with more clinical symptoms may have benefited more from nicotinic effect on PPI.

Altered pre-pulse inhibition in adult rats treated neonatally with domoic acid.

Altered functioning of the glutamate system during critical periods of development is believed to play a role in various neurodevelopmental disorders, such as schizophrenia. Prepulse inhibition (PPI) of the acoustic startle response is deficient in people with schizophrenia. This study investigated the theory that neonatal treatment with domoic acid (DOM), a glutamate agonist, leads to deficient PPI. Results indicate that neonatal treatment with DOM leads to lowered PPI in adult males and an increased startle response in adult females.

Brief post-stressor treatment with pregabalin in an animal model for PTSD: short-term anxiolytic effects without long-term anxiogenic effect.

BACKGROUND: The short- and long-term behavioral effects of a brief course of pregabalin, an antiepileptic structural analogue of alpha-aminobyturic acid with analgesic and anxiolytic effects, were assessed in an animal model of post-traumatic stress disorder (PTSD). METHOD: Two-hundred thirty-three adult male Sprague-Dawley rats were employed. Behavioral responses to traumatic stress exposure (predator urine scent) were assessed immediately after (1 h) and 30 days after treatment with saline or pregabalin (at doses of 30, 100 and 300 mg/kg) in terms of behavior in the elevated plus maze (EPM) and the acoustic startle response (ASR) paradigms. At day 31 the freezing response to a trauma cue (clean cat litter) was assessed. The same treatment regimen initiated at day 7 was assessed at day 30 and in response to the trauma cue on day 31 in a separate experiment. RESULTS: In the short term, doses of 100 mg/kg and 300 mg/kg of pregabalin effectively attenuated anxiety-like behaviors. In the longer-term, pregabalin did not attenuate the onset of PTSD-like behaviors or the prevalence rates of severe cue-responses, for either the immediate or the delayed treatment regimens. CONCLUSION: Pregabalin may present an alternative compound for acute anxiolytic treatment after exposure to trauma, but has no long-term protective/preventive effects.

Effects of anesthesia on DPOAE level and phase in rats.

Many studies of the auditory system are performed on animals under general anesthesia. A concern for researchers is that these agents may significantly alter the underlying neurophysiologic mechanisms being studied. The effects may very across species, and even among individuals within a species. An investigation was undertaken to study whether DPOAE measures differ using three different anesthetic regimens: acetylpromazine-ketamine, xylazine-ketamine, and sodium pentobarbital. The same rat was anesthetized in three consecutive weeks using a different anesthetic regimen each week. DPOAE magnitude and phase temporal responses were recorded from which several measures were taken: DPOAE levels at the onset of the primaries, changes in DPOAE level as a function of time during presentation of the primaries (DeltaLI) and changes in DPOAE level (DeltaLC) and phase (DeltaPC) during presentation of a broad-band noise presented contralateral to the probe. Each week the same measurements were repeated with the rat anesthetized using a different regimen and at the end of the third week, the middle ear muscles were sectioned and the measurements repeated once again. Results showed that the anesthetic regimens did not differentially alter the DPOAE onset levels. When sodium pentobarbital was used as the anesthetic regimen, DeltaLC and DeltaPC were significantly smaller relative to those measured when the rats were anesthetized with acetylpromazine-ketamine and xylazine-ketamine. Based on the assumption that large, positive (DeltaPC) values are related to middle ear muscle activation, the middle ear muscle reflex remained at least partially active in some rats under sodium pentobarbital anesthesia. The DeltaLI measures were significantly smaller when the animals were anesthetized with xylazine-ketamine and sodium pentobarbital than when they were anesthetized with acetylpromazine-ketamine. Recordings taken after sectioning the middle ear muscles suggested that the middle ear muscle reflex substantially contributes to DeltaLC and DeltaPC measures under the anesthetic regimens xylazine-ketamine and acetylpromazine-ketamine. Data indicated that anesthetic agents variably alter neurophysiologic mechanisms involved with the complex control of the auditory signal even among individuals in the same species. Extreme care should be taken when comparing DeltaLI, DeltaLC and DeltaPC across studies when different anesthetic regimens are used within and across species.

Sudden bilateral sensorineural hearing loss following speedballing.

BACKGROUND: Hearing loss is an infrequently-reported consequence of recreational drug abuse. Although there are sporadic reports of hearing loss from heroin and cocaine ingested separately, there are no reports of hearing loss resulting from the combination of both drugs ingested simultaneously in the form of speedballing. PURPOSE: The purpose of this report is to document a case of bilateral sensorineural hearing loss associated with an episode of speedballing. RESEARCH DESIGN: Case Report. DATA COLLECTION AND ANALYSIS: The subject of this report was a 40-year-old man with a 20-year history of substance abuse. Data collected included a case history, pure tone audiometry, tympanometry and acoustic reflexes, and transient evoked otoacoustic emissions. RESULTS: The audiologic evaluation indicated a mild to moderate, relatively flat, bilateral sensorineural hearing loss that was worse in the right ear. CONCLUSIONS: A bilateral sensorineural hearing loss involving both cochlear and neural pathology may be a rare complication of cocaine, heroin, or the combination of the two drugs.

A Clinical Trial of Proton Pump Inhibitors to Treat Children with Chronic Otitis Media with Effusion.

OBJECTIVE: Gastroesophageal reflux (GER) is considered a cause of otitis media with effusion (OME). This study aimed to investigate whether OME can be effectively treated with a proton pump inhibitor (PPI), therefore implicating GER as a causative factor of OME. MATERIALS AND METHODS: A PPI or placebo was randomly administered to enrolled subjects for 4-8 weeks. To monitor effusion status, subjects underwent monthly pneumatic otoscopy and acoustic reflectometry. At enrollment and at completion of treatment, subjects underwent an audiogram and tympanogram for assessing changes in hearing due to altered fluid levels in the middle ear. After the treatment period, tympanostomy tube placement was recommended for subjects with unresolved effusion. RESULTS: This study enrolled 16 patients with an average age of 5.17 years. Between the treatment and placebo groups, there was no significant difference in the need for tympanostomy tubes. At completion of this study, patients receiving Lansoprazole demonstrated a significant improvement in pure tone average (p<0.01) and speech recognition thresholds (p=0.04). Four patients (25%) from the cohort dropped out of the study. Eight patients (50%) from the cohort required tympanostomy tube placement. CONCLUSION: Owing to difficulties with recruitment and small sample size, this study was unable to demonstrate the use of PPI in treating OME. A larger study is needed for further evaluation of this process.

Pharmacological Rescue of Hippocampal Fear Learning Deficits in Fragile X Syndrome.

Fragile X Syndrome (FXS) is the leading cause of autism spectrum disorder and intellectual disability and results from loss of Fragile X mental retardation protein (FMRP). In neurons, FMRP controls the translation of synaptic plasticity proteins that are implicated in learning and memory. FMRP also regulates development- and experience-dependent actin cytoskeleton remodeling within dendritic spines through the small Rho GTPase Rac1. Modulation of Rac1 activity is critical during synaptic plasticity as well as learning and memory. We have previously shown that FXS mouse models exhibit learning and memory deficits as well as hyperactive Rac1 in the hippocampus. To determine whether pharmacological inhibition of Rac1 in FXS improves cognitive impairment, FXS mice were treated with the specific Rac1 inhibitor NSC23766, followed by fear conditioning. Whereas non-cognitive functions were unaffected, hippocampus-related memory improved in FXS mice treated with the Rac1 inhibitor. Furthermore, long-term potentiation in hippocampal slices from FXS mice was increased after incubation with the Rac1 inhibitor. Together, these observations indicate that modulation of Rac1 may provide a novel therapeutic target in the treatment of cognitive impairment in FXS.

Repeated shock stress facilitates basolateral amygdala synaptic plasticity through decreased cAMP-specific phosphodiesterase type IV (PDE4) expression.

Previous studies have shown that exposure to stressful events can enhance fear memory and anxiety-like behavior as well as increase synaptic plasticity in the rat basolateral amygdala (BLA). We have evidence that repeated unpredictable shock stress (USS) elicits a long-lasting increase in anxiety-like behavior in rats, but the cellular mechanisms mediating this response remain unclear. Evidence from recent morphological studies suggests that alterations in the dendritic arbor or spine density of BLA principal neurons may underlie stress-induced anxiety behavior. Recently, we have shown that the induction of long-term potentiation (LTP) in BLA principal neurons is dependent on activation of postsynaptic D1 dopamine receptors and the subsequent activation of the cyclic adenosine 5'-monophosphate (cAMP)-protein kinase A (PKA) signaling cascade. Here, we have used in vitro whole-cell patch-clamp recording from BLA principal neurons to investigate the long-term consequences of USS on their morphological properties and synaptic plasticity. We provided evidence that the enhanced anxiety-like behavior in response to USS was not associated with any significant change in the morphological properties of BLA principal neurons, but was associated with a changed frequency dependence of synaptic plasticity, lowered LTP induction threshold, and reduced expression of phosphodiesterase type 4 enzymes (PDE4s). Furthermore, pharmacological inhibition of PDE4 activity with rolipram mimics the effects of chronic stress on LTP induction threshold and baseline startle. Our results provide the first evidence that stress both enhances anxiety-like behavior and facilitates synaptic plasticity in the amygdala through a common mechanism of PDE4-mediated disinhibition of cAMP-PKA signaling.

Characterization of Behavioral, Signaling and Cytokine Alterations in a Rat Neurodevelopmental Model for Schizophrenia, and Their Reversal by the 5-HT6 Receptor Antagonist SB-399885.

Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT6 receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister hooded rats (weaned on post-natal days 21-24 and housed individually or in groups of 3-4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a 2-week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFα levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms.

Antagonism of nucleus accumbens M(2) muscarinic receptors disrupts operant responding for sucrose under a progressive ratio reinforcement schedule.

Diverse cholinergic signaling mechanisms regulate the excitability of striatal principal neurons and modulate striatal-dependent behavior. These effects are mediated, in part, by action at muscarinic receptors (mAChR), subtypes of which exhibit distinct patterns of expression across striatal neuronal populations. Non-selective mAChR blockade within the nucleus accumbens (NAc) has been shown to disrupt operant responding for food and to inhibit food consumption. However, the specific receptor subtypes mediating these effects are not known. Thus, we evaluated effects of intra-NAc infusions of pirenzepine and methoctramine, mAChR antagonisits with distinct binding affinity profiles, on operant responding for sucrose reward under a progressive ratio (PR) reinforcement schedule. Moderate to high doses of methoctramine disrupted operant responding and reduced behavioral breakpoint. In contrast, pirenzepine failed to impact operant performance at any dose tested. Methoctramine failed to affect latencies to complete appetitive-consummatory response sequences or to impact measures of acoustic startle, suggesting that its' disruptive effects on operant behavior were not consequent to gross motor impairment. Since methoctramine has a greater affinity for M(2) receptors compared to pirenzepine, which has a greater relative affinity for M(1) and M(3) receptors, these findings suggest that M(2) mAChRs within the NAc regulate behavioral processes underling the acquisition of reward.

Increase in cochlear microphonic potential after toluene administration.

Human and animal studies have shown that toluene can cause hearing loss. In the rat, the outer hair cells are first disrupted by the ototoxicant. Because of their particular sensitivity to toluene, the cochlear microphonic potential (CMP) was used for monitoring the cochlea activity of anesthetized rats exposed to both noise (band noise centered at 4 kHz) and toluene. In the present experiment, the conditions were specifically designed to study the toluene effects on CMP and not those of its metabolites. To this end, 100-microL injections of a vehicle containing different concentrations of solvent were made into the carotid artery connected to the tested cochlea. Interestingly, an injection of 116.2-mM toluene dramatically increased in the CMP amplitude (approximately 4 dB) in response to an 85-dB SPL noise. Moreover, the rise in CMP magnitude was intensity dependent at this concentration suggesting that toluene could inhibit the auditory efferent system involved in the inner-ear or/and middle-ear acoustic reflexes. Because acetylcholine is the neurotransmitter mediated by the auditory efferent bundles, injections of antagonists of cholinergic receptors (AchRs) such as atropine, 4-diphenylacetoxy-N-methylpiperidine-methiodide (mAchR antagonist) and dihydro-beta-erythroidine (nAchR antagonist) were also tested in this investigation. They all provoked rises in CMP having amplitudes as large as those obtained with toluene. The results showed for the first time in an in vivo study that toluene mimics the effects of AchR antagonists. It is likely that toluene might modify the response of protective acoustic reflexes.

Solvent-induced hearing loss: mechanisms and prevention strategy.

While noise exposure is the most significant contributor to occupational hearing loss, evidence gained over the last 10 years, has pointed to organic solvents as additional contributors to occupational hearing disorders. Despite the implications of this finding, no significant measure has been undertaken to limit exposure to occupational solvents, or to occupational solvents and noise, within the European community. Guidelines for improving hearing protection of people exposed to solvents, or to solvents and noise, are addressed in the present article. Recently, it has been shown that the lowest-observed-adverse-effect level (LOAEL) of styrene was 300 ppm in active (working wheel) rats, and that the same amount of styrene-induced hearing loss (SIHL) can be obtained with styrene concentration difference of 200 ppm between active and sedentary (inactive) rats. Supported by a reasonable safety factor (SF) of 10, the authors proposed to decrease the French threshold limit value of styrene from 50 to 30 ppm (RfD=LOAEL/SF) to ensure a higher level of protection for human hearing. It is widely acknowledged that outer hair cells in the organ of Corti can be considered as the first target tissue of solvents, while little is known about the action of aromatic solvents on the auditory efferent system. In a recent experiment using both the cochlear microphonic and compound action potentials, the authors have shown that toluene can inhibit the action of the middle ear reflex by modifying the cholinergic receptors. It is likely that toluene affects the cholinergic receptors at the brainstem level. By its anticholinergic-like effect, toluene could allow higher acoustic energy penetration into the cochlea exposed to both noise and solvent. Based on this phenomenon, the authors recommend the use of hearing protection for the lower exposure action value: Lex,8h=80 dB(A) in noisy environments polluted by solvents.